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Journal of Immunology (Baltimore, Md. :... Apr 2024Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in...
Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in hematopoiesis and the possible pathological role of Fosl2 inactivation in the hematopoietic system in arthritis. In this study, we show that Fosl2 maintains hematopoietic stem cell (HSC) quiescence and differentiation while controlling the inflammatory response via macrophages. Fosl2-specific deletion in the hematopoietic system caused the expansion of HSCs and myeloid cell growth while affecting erythroid and B cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. Loss of Fosl2 mediated by Vav-iCre also displays an unexpected deletion in embryonic erythro-myeloid progenitor-derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in Vav-iCreFosl2f/f mice is a consequence of the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. Thus, Fosl2 is indispensable for erythro-myeloid progenitor-derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis. These findings improve our understanding of the pathogenesis of bone-destructive diseases and provide important implications for developing therapeutic approaches for these diseases.
Topics: Animals; Mice; Arthritis; Bone Marrow Failure Disorders; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Osteopetrosis; Fos-Related Antigen-2
PubMed: 38380993
DOI: 10.4049/jimmunol.2300592 -
Journal of Cell Science Feb 2024Microglia, professional phagocytic cells of the brain, rely upon the appropriate activation of lysosomes to execute their immune and clearance functions. Lysosomal...
Microglia, professional phagocytic cells of the brain, rely upon the appropriate activation of lysosomes to execute their immune and clearance functions. Lysosomal activity is, in turn, modulated by a complex network of over 200 membrane and accessory proteins that relay extracellular cues to these key degradation centers. The ClC-7 chloride (Cl-)-proton (H+) antiporter (also known as CLCN7) is localized to the endolysosomal compartments and mutations in CLCN7 lead to osteopetrosis and neurodegeneration. Although the functions of ClC-7 have been extensively investigated in osteoclasts and neurons, its role in microglia in vivo remains largely unexamined. Here, we show that microglia and embryonic macrophages in zebrafish clcn7 mutants cannot effectively process extracellular debris in the form of apoptotic cells and β-amyloid. Despite these functional defects, microglia develop normally in clcn7 mutants and display normal expression of endosomal and lysosomal markers. We also find that mutants for ostm1, which encodes the β-subunit of ClC-7, have a phenotype that is strikingly similar to that of clcn7 mutants. Together, our observations uncover a previously unappreciated role of ClC-7 in microglia and contribute to the understanding of the neurodegenerative phenotypes that accompany mutations in this channel.
Topics: Animals; Microglia; Membrane Proteins; Chlorides; Zebrafish; Protons; Phagocytes; Chloride Channels
PubMed: 38294065
DOI: 10.1242/jcs.261616 -
The Journal of Clinical Endocrinology... Apr 2024Autosomal dominant osteopetrosis (ADO) is a rare sclerotic bone disease characterized by impaired osteoclast activity, resulting in high bone mineral density and...
CONTEXT
Autosomal dominant osteopetrosis (ADO) is a rare sclerotic bone disease characterized by impaired osteoclast activity, resulting in high bone mineral density and skeletal fragility. The full phenotype and disease burden on patients' daily lives has not been systematically measured.
OBJECTIVE
We developed an online registry to ascertain population-based data on the spectrum and rate of progression of disease and to identify relevant patient centered outcomes that could be used to measure treatment effects and guide the design of future clinical trials.
DESIGN
Cross-sectional data from participants with osteopetrosis were collected using an online REDCap-based database.
PARTICIPANTS
Thirty-four participants with a confirmed diagnosis of ADO, aged 4-84 years.
MAIN OUTCOME MEASURES
Participants aged 18 years and older completed the PROMIS 57, participants aged 8 to 17 years completed the PROMIS Pediatric 49, and parents of participants aged <18 years completed the PROMIS Parent Proxy 49.
RESULTS
Based on the PROMIS 57, relative to the general population, adults with ADO reported low physical function and low ability to participate in social roles and activities, and high levels of anxiety, fatigue, sleep problems, and pain interference. Daily pain medications were reported by 24% of the adult population. In contrast, neither pediatric participants, nor their parent proxy reported a negative impact on health-related quality of life.
CONCLUSIONS
Data from this registry demonstrate the broad spectrum of ADO disease severity and high impact on health-related quality of life in adults with ADO.
PubMed: 38661205
DOI: 10.1210/clinem/dgae285 -
Intractable & Rare Diseases Research Aug 2023We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome....
We performed a study to present a phenotypic and genotypic characterization of a patient clinically diagnosed with carbonic anhydrase II (CAII) deficiency syndrome. Medical records were reviewed, and oral examination was performed. Sanger sequencing was undertaken for molecular diagnosis. The patient presented with osteopetrosis, renal tubular acidosis, cerebral calcification, blindness, deafness, and development delay. The oral manifestations included anterior open bite, posterior crossbite, tooth eruption impairment, and hypoplastic amelogenesis imperfecta (AI). Molecular analysis revealed a homozygous deletion (c.753delG, p.Asn252Thrfs*14) and confirmed the clinical diagnosis. This study suggests that AI can be another feature of CAII deficiency syndrome. For the first time, a disease-causing variant is reported to be associated with syndromic AI.
PubMed: 37662627
DOI: 10.5582/irdr.2023.01033 -
BMJ Case Reports Oct 2023Osteopetrosis encompasses a spectrum of conditions marked by heightened bone density due to faulty osteoclast-mediated bone resorption, leading to an accumulation of...
Osteopetrosis encompasses a spectrum of conditions marked by heightened bone density due to faulty osteoclast-mediated bone resorption, leading to an accumulation of immature bone and thickened cortical structures. This condition gives rise to bone fragility, blood cell irregularities, nerve entrapment and growth challenges, all stemming from disrupted bone remodelling. Craniofacial distinctiveness, encompassing anomalies in the skull and jaw, is a frequent occurrence. Osteopetrosis presents a range of clinical signs, including facial and dental anomalies. The diagnostic process involves thorough clinical and radiological assessments, often obviating the need for genetic testing. Interestingly, few prior reports have delved into the specifics of craniofacial and dental issues in osteopetrosis. The presented case showcases rare occurrence of maxillary osteomyelitis. The diagnosis was established through a combination of history, clinical, radiographic and laboratory findings. The patient declined surgical intervention, leading to the implementation of conservative management involving regular irrigation alongside systemic antibiotic therapy.
Topics: Humans; Female; Osteopetrosis; Osteomyelitis; Maxilla; Skull; Bone Density
PubMed: 37907307
DOI: 10.1136/bcr-2023-257908 -
The Journal of the Association of... Jul 2023
Topics: Adult; Humans; Osteopetrosis
PubMed: 37449700
DOI: No ID Found -
Journal of Pediatrics. Clinical Practice Mar 2024We present a newborn with transient generalized osteosclerosis and negative genetic workup. The etiology of this condition is unknown. Given overlapping radiologic signs...
We present a newborn with transient generalized osteosclerosis and negative genetic workup. The etiology of this condition is unknown. Given overlapping radiologic signs with severe forms of osteopetrosis, familiarity with this condition is crucial for correct diagnosis and management.
PubMed: 38827482
DOI: 10.1016/j.jpedcp.2024.200100 -
JBJS Case Connector Apr 2024Two patients with osteopetrosis underwent conversion total hip arthroplasty (THA) after failure of internal fixation due to hip fractures. We experienced challenges,...
CASE
Two patients with osteopetrosis underwent conversion total hip arthroplasty (THA) after failure of internal fixation due to hip fractures. We experienced challenges, including difficulty of hardware removal, remaining of previous broken screws in the canal, difficulty in finding the femoral canal, and an intraoperative acetabulum fracture. Despite complications, both patients achieved satisfactory functional outcome after surgery at the latest follow-up.
CONCLUSION
Our cases showed that previous hip fracture and failed internal fixation make conversion THA more complex and unpredictable in patients with osteopetrosis. This in turn underscores the critical need for advanced preoperative planning, intraoperative flexibility, and meticulous postoperative care.
Topics: Humans; Arthroplasty, Replacement, Hip; Osteopetrosis; Female; Hip Fractures; Male; Middle Aged; Fracture Fixation, Internal; Aged
PubMed: 38728525
DOI: 10.2106/JBJS.CC.23.00583 -
Journal of Comparative Pathology Jul 2023Tracheal luminal stenosis can cause clinical respiratory distress in wild birds. We describe a case of tracheal stenosis due to diffuse ossification with osteopetrosis...
Tracheal luminal stenosis can cause clinical respiratory distress in wild birds. We describe a case of tracheal stenosis due to diffuse ossification with osteopetrosis of tracheal rings in a yellow-crowned parrot (Amazona ochrocephala) with a history of chronic respiratory distress and death after development of marked dyspnoea. An ante-mortem radiographic examination revealed that the tracheal rings were radiopaque and that there were multiple areas of osteopenic change in long bones. At necropsy, there was stenosis of the tracheal rings characterized by complete replacement of cartilage by thickened compact bone with osteopetrosis and bone necrosis. The clinical respiratory distress and death of the parrot were associated with tracheal luminal stenosis due to thickening of the tracheal rings by diffuse ossification with osteopetrosis.
Topics: Animals; Amazona; Tracheal Stenosis; Osteogenesis; Constriction, Pathologic; Osteopetrosis; Bird Diseases; Respiratory Distress Syndrome
PubMed: 37311267
DOI: 10.1016/j.jcpa.2023.05.003 -
Journal of Sleep Research Oct 2023Children with genetic skeletal disorders have variable conditions that can lead to sleep-disordered breathing, and polysomnography is the gold standard for diagnosing...
Children with genetic skeletal disorders have variable conditions that can lead to sleep-disordered breathing, and polysomnography is the gold standard for diagnosing this condition. We aimed to review polysomnography findings, to assess the severity of sleep apnea, and to investigate the clinical variables predictive of sleep-disordered breathing in these patients. We retrospectively collected the medical records of patients with genetic skeletal disorders who underwent polysomnography for 5 years. Twenty-seven children with various genetic skeletal disorders, including achondroplasia (14), Crouzon syndrome (3), acromesomelic dysplasia Maroteaux type (3), Apert syndrome (2), osteopetrosis (1), Jeune dysplasia (1), Desbuquois dysplasia (1), acrodysostosis (1), and spondyloepiphyseal dysplasia (1) were enrolled. The median age at the first polysomnography was 58 (1st-3rd quartile: 31-113) months. The overall sleep-disordered breathing results were: 19 (70.3%) had obstructive sleep apneas (OSA) (4 mild, 6 moderate, 9 severe), 2 (7.4%) had central apneas, 4 (14.8%) had nocturnal hypoventilation. There was a significant correlation between non-ambulatory status with both total AHI and OSA (p < 0.001, rho: -0.66/p = 0.04, rho: 0.38, respectively). Nine patients received positive airway pressure titration, and the oAHI values of all returned to the normal range. These patients were started with positive airway pressure treatment. Our cohort showed that the majority of the patients with skeletal dysplasia had sleep apnea syndrome characterised mainly by OSA, highlighting the importance of polysomnography screening for sleep disorders. Positive airway pressure therapy represents an effective treatment for sleep-disordered breathing in those patients.
Topics: Humans; Child; Child, Preschool; Retrospective Studies; Polysomnography; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Sleep Apnea, Central
PubMed: 37128177
DOI: 10.1111/jsr.13914